RESUMO
Previously, we have suggested that vascular cell adhesion molecule-1 (VCAM-1) and its integrin receptor alpha4beta1 mediate cell-cell interactions important for skeletal myogenesis. Expression of the receptors subsequently subsides in muscle after birth. Here, we examine the mechanism regulating VCAM-1 gene expression in muscle. An enhancer located between the TATA box and the transcriptional start site is responsible for VCAM-1 gene expression in muscle-this element is inactive in endothelial cells where VCAM-1 expression is dependent on nuclear factor kappaB sites and inflammatory cytokines. We identify interferon regulatory factor-2 (IRF-2), a member of the interferon regulatory factor family, as the enhancer-binding transcription factor and show that expression of IRF-2 parallels that of VCAM-1 during mouse skeletal myogenesis. IRF-2 is not dependent upon cytokines for expression or activity, and it has been shown to act as a repressor in other nonmuscle cell types. We show that the basic repressor motif located near the COOH-terminal of IRF-2 is not active in muscle cells, but instead an acidic region in the center of the molecule functions as a transactivating domain. Although IRF-2 and VCAM-1 expression diminishes on adult muscle fiber, they are retained on myogenic stem cells (satellite cells). These satellite cells proliferate and fuse to regenerate muscle fiber after injury or disease. We present evidence that VCAM-1 on satellite cells mediates their interaction with alpha4beta1(+) leukocytes that invade the muscle after injury or disease. We propose that VCAM-1 on endothelium generally recruits leukocytes to muscle after injury, whereas subsequent interaction with VCAM-1 on regenerating muscle cells focuses the invading leukocytes specifically to the sites of regeneration.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Músculo Esquelético/metabolismo , Proteínas Repressoras , Transativadores , Fatores de Transcrição , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Comunicação Celular , Linhagem Celular , Proteínas de Ligação a DNA/biossíntese , Regulação para Baixo , Distrofina/metabolismo , Integrina alfa4beta1 , Integrinas/metabolismo , Fator Regulador 2 de Interferon , Leucócitos/metabolismo , Camundongos , Mutagênese , Regiões Promotoras Genéticas , Receptores de Retorno de Linfócitos/metabolismo , Regeneração , Células-Tronco , TATA Box , Ativação Transcricional , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Cells interact with extracellular fibronectin (FN) via adhesive fibronectin receptors (FNRs) that are members of the very late antigens (VLAs) subgroup of the integrin family. In stationary fibroblasts, the FNR is highly organized and distributed identically to extracellular FN fibrils. However, in highly migratory neural crest cells and embryonic somatic fibroblasts, this organization is lost and the FNR appears diffuse. Similarly, oncogenic transformation typically leads to disorganization of the FN receptor and loss of matrix FN. Two models can account for these observations. First, the FN matrix may organize the FN receptor at extracellular matrix contacts on the cell surface. Motile cells not depositing FN matrices thus lack organized receptors. Alternatively, as the FNR is required for optimal FN matrix assembly, (McDonald, J. A., B. J. Quade, T. J. Broekelmann, R. LaChance, K. Forseman, K. Hasegawa, and S. Akiyama. 1987. J. Biol. Chem. 272:2957-2967; Roman, J. R. M. LaChance, T. J. Broekelmann, C. J. R. Kennedy, E. A. Wayner, W. G. Carter, J. A. McDonald. 1989. J. Cell Biol. 108:2529-2543) and has putative cytoskeletal links, it could be organized from within the cell helping to position newly forming FN fibrils. To study this question, we developed peptide antibodies specifically recognizing the alpha 5 subunit of the FNR. Using these antibodies, we examined the organization of FN and of the FNR in normal, matrix assembly inhibited, and SV40-transformed human fibroblasts. On FN-coated substrates, the FNR is found in focal contacts rather than diffusely on the basal cell surface, suggesting FNR interaction with intracellular components. However, when FN fibrils are deposited, the FNR is co-distributed with these fibrils. Preventing FN matrix assembly prevents organization of the FNR. Moreover, when fibroblasts with well established FN matrices and co-distributed FNR are incubated briefly with monoclonal antibodies that block FNR binding to FN, the FNR is no longer co-distributed with the FN matrix. Thus, the FN receptor is organized in fibrils on the cell surface in response to extracellular FN. Because exogenous FN restores a FN matrix and receptor organization to SV40-transformed cells, the diffuse FN receptor phenotype appears to be related to loss of the FN matrix rather than to impaired FNR function. These results explain diffusely distributed FNRs in migratory neural crest and embryonic fibroblasts lacking well organized FN matrices and emphasize the existence of separate but related systems controlling FN deposition and recognition by receptor-armed cells.
Assuntos
Adesão Celular , Membrana Celular/ultraestrutura , Matriz Extracelular/fisiologia , Fibronectinas/fisiologia , Receptores Imunológicos/fisiologia , Linhagem Celular , Transformação Celular Viral , Citocalasina B/farmacologia , Citoesqueleto/fisiologia , Imunofluorescência , Glicoproteínas/fisiologia , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/imunologia , Receptores de Fibronectina , Receptores Imunológicos/imunologia , Receptores Imunológicos/ultraestrutura , Receptores de Vitronectina , Vírus 40 dos Símios , Relação Estrutura-Atividade , VitronectinaRESUMO
Somatostatin, at concentrations up to 10(-7) M, does not inhibit the basal release of TSH from primary cultures of rat anterior pituitary cells. The TRH-induced TSH release is however 65% reduced by somatostatin, half-maximal inhibition being measured at 2.5 x 10(-10) M somatostatin. The concentration of TRH giving half-maximal stimulation (ED50) of TSH release is only slightly increased from 1 to 3 x 10(-9) M in the presence of 10(-8) M somatostatin. Somatostatin inhibits by 45-65% both the basal and TRH-induced PRL release of pituitary cells prepared from adult female rats, with half-maximal inhibition at approximately 5 x 10(-10) M somatostatin. The TRH ED50 for PRL release was not significantly affected by somatostatin. Somatostatin (200 mug) has no effect on the basal plasma levels of TSH or PRL in anesthetized male rats treated with estradiol benzoate (EB), hypothyroid rats, or hypothyroid animals treated with EB. The plasma TSH response to TRH is, however, reduced by approximately 75% by somatostatin while the plasma PRL response is not affected by injection of the peptide. The interaction between TRH and somatostatin for both TSH and PRL release is non-competitive and is thus likely to occur at a step subsequent to the binding of the peptides to their specific receptors in both thyrotrophs and mammotrophs.
Assuntos
Adeno-Hipófise/metabolismo , Hipófise/metabolismo , Prolactina/metabolismo , Somatostatina/farmacologia , Hormônio Liberador de Tireotropina/farmacologia , Tireotropina/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Estradiol/farmacologia , Feminino , Masculino , Adeno-Hipófise/citologia , Prolactina/sangue , Propiltiouracila/farmacologia , Ratos , Tireotropina/sangue , Tiroxina/farmacologiaRESUMO
We recently reported almost complete disappearance of serum LH biological activity in previously untreated patients with advanced prostatic cancer receiving combined therapy with a LHRH agonist and a pure antiandrogen. This decrease in LH bioactivity was most likely responsible for the fall of circulating testosterone to castration levels during such treatment. Since patients previously treated with high doses of estrogens or orchiectomy before receiving combined therapy had a less favorable response to the new treatment, we measured serum LH levels by RIA and the mouse interstitial cell bioassay in these 2 groups of patients. Serum samples were obtained from 14 men with advanced prostatic cancer treated from 9-41 months (24 +/- 9 months) with diethylstilbestrol before receiving 500 micrograms/day LHRH agonist ([D-Trp6]LH/RH ethylamide) in combination with 3 daily oral doses of 250 mg pure antiandrogen flutamide and from 21 men castrated for at least 9 months (32 +/- 26 months) before receiving the antiandrogen alone. In previously castrated patients, both bio- and immunoactive LH serum levels were elevated and did not change during at least 3 months of antiandrogen treatment. In estrogen-pretreated men, however, bioactive LH concentrations declined from 1.2 +/- 0.5 (+/- SEM) to 0.04 +/- 0.01 ng/ml after 1 month of combined treatment and remained low thereafter, while serum LH levels, measured by RIA, did not significantly decline (1.4 +/- 0.5 vs. 0.9 +/- 0.1 ng/ml on days--2 and 30, respectively). This decrease in LH biopotency caused the biological to immunological activity ratio to fall from 0.5 +/- 0.2 before the onset of the combined therapy to 0.05 +/- 0.01 after 3 months. Thus, estrogen pretreatment did not prevent the ability of the LHRH agonist-antiandrogen combination to decrease serum LH biological activity. Moreover, the absence of an effect in castrated patients receiving antiandrogen alone indicates that the LHRH agonist, and not flutamide, was responsible for the effects of the combined therapy.
Assuntos
Anilidas/uso terapêutico , Dietilestilbestrol/uso terapêutico , Flutamida/uso terapêutico , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Luteinizante/sangue , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Pamoato de Triptorrelina/análogos & derivados , Idoso , Bioensaio , Terapia Combinada , Quimioterapia Combinada , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue , Neoplasias da Próstata/cirurgia , Radioimunoensaio , Fatores de TempoRESUMO
This study was performed on two groups of schizophrenic patients. One group consisted on nine nonlobotomized patients and the other of nine lobotomized ones. The groups were matched for age, sex, duration of illness, clinical symptoms, type and dose of psychopharmacological treatment. The patients of both groups were administered 1 mg of reserpine half an hour before bedtime, for three successive days. Before reserpine administration the mean percentage time of the NREM stage 4 was significantly higher in the lobotomized group. There was no significant difference in the REM parameters. After three days of reserpine administration in the nonlobotomized group, there was no significant difference in the mean percentage of the NREM stage 4, whereas the mean REM percentage significantly increased and REM latency decreased. In the lobotomized group the same procedure, i.e., three days of reserpine administration, provoked a significant decrease in the mean percentage of the NREM stage 4 and no significant changes in the REM parameters. This difference in reserpine action on sleep in the lobotomized group is discussed.
Assuntos
Psicocirurgia , Reserpina/farmacologia , Esquizofrenia/cirurgia , Sono/efeitos dos fármacos , Doença Crônica , Sonhos/efeitos dos fármacos , Eletrocardiografia , Eletroencefalografia , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sono REM/efeitos dos fármacos , Fatores de Tempo , VigíliaRESUMO
The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E(1)S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17alpha of estradiol (E(2)), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17alpha-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17alpha-decyl-E(2) and 17alpha-dodecyl-E(2), a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC(50) = 440 nM), but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17alpha-(benzyl substituted)-E(2) derivatives studied, the 3'-bromobenzyl, 4'-tert-butylbenzyl, 4'-butylbenzyl, and 4'-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E(1)S into E(1) (IC(50) = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E(2) nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E(1)S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).
Assuntos
Arilsulfatases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Estradiol/análogos & derivados , Estradiol/síntese química , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estradiol/química , Estradiol/farmacologia , Humanos , Esteril-Sulfatase , Relação Estrutura-Atividade , TransfecçãoRESUMO
In two experiments, 64 crossbred ewes that had lambed in September or January and had their lambs removed within 24 h after birth were assigned to four groups and given the following treatments: group 1 (16 ewes)-1 ml saline, im or iv on d 10 postpartum; group 2 (24 ewes)-150 microgram/gonadotropin releasing hormone (GnRH) in 1 ml saline, im or iv on d 10 postpartum; group 3 (16 ewes)-150 microgram/GnRH in 1 ml saline, im or iv on d 10 postpartum, plus 40 mg fluorogestone acetate (FGA)-impregnated intravaginal sponges for 12 d beginning 22 d postpartum and group 4 (eight ewes)-40 mg FGA-impregnated intravaginal sponges only for 12 d beginning 22 d postpartum. Pregnant mare's serum gonadotropin (500 IU) was injected im into FGA-treated ewes at the time of sponge removal. Blood samples were collected from eight ewes in groups 1 and 2 at regular intervals up to 2 and 6 h, respectively, after treatment and analysed for luteinizing hormone (LH). Plasma progesterone (P) levels in blood collected once or twice weekly were used to monitor ovarian activity. GnRH induced a release of LH in all ewes monitored, whereas the LH levels remained unchanged in saline-treated ewes. Only 44% of the latter ewes had shown evidence of luteal activity by 50 d postpartum. The mean plasma P levels in the GnRH-treated ewes did not rise above basal preinjection values during the 14 d after treatment. In contrast, a synchronized ovulation followed by normal luteal activity was induced in 88% of the FGA-sponge-treated ewes. Of 16 ewes from group 2 slaughtered 26 d postpartum, 13 had ovaries that contained luteinized structures and uterine involution was incomplete in six ewes. These results preclude the use of GnRH as a single injection for induction of cyclic ovarian activity in the early postpartum ewe and indicate the need for progestogen treatment to initiate cyclic ovarian activity by 35 d postpartum. However, incomplete uterine involution may limit the number of ewes that can be successfully rebred at this time.
Assuntos
Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Luteinizante/sangue , Ovário/efeitos dos fármacos , Período Pós-Parto , Ovinos/fisiologia , Animais , Corpo Lúteo/anatomia & histologia , Feminino , Gravidez , Progesterona/sangue , Útero/fisiologiaRESUMO
Uses of health information systems depend heavily on the background and experiences of those who evaluate the data. Effective collaboration between physicians and system managers can enhance significantly the decision-making and information obtained from these systems. This article describes some methods of collaboration and the current uses of one system developed through collaborative efforts of physicians and system managers.
Assuntos
Medicina de Família e Comunidade , Sistemas de Informação , Internato e Residência/organização & administração , Assistência Ambulatorial , Técnicas de Laboratório Clínico/estatística & dados numéricos , Medicina de Família e Comunidade/educação , Revisão da Utilização de Recursos de Saúde/métodosAssuntos
Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Feminino , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Ácidos Palmíticos/administração & dosagem , Ácidos Palmíticos/efeitos adversos , Ácidos Palmíticos/uso terapêutico , Fenotiazinas , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Esquizofrenia Hebefrênica/tratamento farmacológico , Esquizofrenia Paranoide/tratamento farmacológico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Ácidos Undecilênicos/uso terapêuticoAssuntos
Secobarbital/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Ureia/uso terapêutico , Adulto , Transtorno Bipolar/complicações , Doença Crônica , Ensaios Clínicos como Assunto , Tolerância a Medicamentos , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Métodos , Pessoa de Meia-Idade , Placebos , Esquizofrenia/complicações , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/complicaçõesRESUMO
In order to maximize the benefits of a multimodal therapeutic regime, a therapeutic group milieu setting is needed as a catalyst, followed by mandatory community care. Therefore, the treatment of choice for the psychopath seems to be the integrated comprehensive approach on a long term basis. However, should therapy be ineffective, the structure will be maintained while the elapse of time decreases the psychopathic behaviour to a virtual non-existent entity as a result of aging. In either case, society will be protected.
Assuntos
Agressão , Transtorno da Personalidade Antissocial/terapia , Adolescente , Adulto , Transtorno da Personalidade Antissocial/psicologia , Humanos , Terapia AmbientalRESUMO
Current views of the pathogenesis of Potter's syndrome of renal agenesis are discussed. Embryological, teratological and genetic associations between kidney and limb development are reviewed. An infant is described with lobsterclaw deformity of the hands and feet, renal hypoplasia and the Potter face.
Assuntos
Anormalidades Múltiplas/etiologia , Expressão Facial , Rim/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/patologia , Adulto , Líquido Amniótico , Animais , Galinhas , Feminino , Humanos , Recém-Nascido , Rim/patologia , Deformidades Congênitas dos Membros , Mesoderma/crescimento & desenvolvimento , Camundongos , Radiografia , Suínos , Síndrome , Útero/anormalidadesRESUMO
It is now well recognized that hCG-induced luteolysis is associated with hCG-induced desensitization, but the physiological significance of luteal cell GnRH, PGs and beta-receptors is still undefined. Therefore, we intend in this study to observe the effects of prostaglandin F2 alpha and prostaglandin E2 and the interactions between epinephrine, a potent LHRH agonist [(D-Ser-(TBu)6, des-Gly-NH10(2) LHRH ethylamide: Buserelin] and hCG in normal and in vitro hCG-desensitized rat immature luteal cells in monolayer culture, on basal, hCG or cholera toxin stimulated intracellular and extracellular cAMP and progesterone secretion. The present report shows that incubation of immature rat luteal cells in monolayer culture with Buserelin, led to 25-50% inhibition of the epinephrine-as well as PGE2-induced cAMP and progesterone responses. The LHRH agonist can also reverse the stimulatory effects of cholera toxin in the presence of hCG and led with PGF2 alpha, to additive inhibitory effects on extracellular cAMP accumulation induced by cholera toxin. Both Buserelin and PGF2 alpha can reverse the hCG-induced cAMP and progesterone release but no effect could be observed when the incubation was carried out with either substance in the absence of hCG. Prostaglandin E2, in acute conditions of incubation, seems to share agonist properties with hCG when both were incubated with luteal cells. Buserelin reversed the stimulatory effects of PGE2, hCG, epinephrine and cholera toxin on cAMP and progesterone responses to these substances. These results suggest that Buserelin and PGF2 alpha have luteolytic-like effects and that there may be a complementary action for the two substances. Preincubation of rat luteal cells in monolayer culture with 1 nM hCG for a 24 h period led to the inhibition of cAMP and progesterone responses after a subsequent exposure to hCG and epinephrine. Luteal cells were no longer responsive to hCG while the presence of epinephrine in hCG-desensitized cells led to a 40% stimulation of cAMP and progesterone production. These observations suggest that occurred a partial alteration of the N component activity of the adenylyl cyclase system.
Assuntos
Busserrelina/farmacologia , Gonadotropina Coriônica/farmacologia , Corpo Lúteo/metabolismo , Epinefrina/farmacologia , Prostaglandinas/farmacologia , Animais , Células Cultivadas , Corpo Lúteo/efeitos dos fármacos , AMP Cíclico/biossíntese , Dinoprosta , Dinoprostona , Feminino , Progesterona/metabolismo , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologia , Radioimunoensaio , Ratos , Ratos EndogâmicosRESUMO
It is now well recognized that hCG-induced luteolysis is associated with hCG-induced desensitization, but the physiological significance of luteal cell GnRH, PGS and beta-receptors is still undefined. Therefore, we intend in this study to observe the effects of prostaglandin F2 alpha and prostaglandin E2 and the interactions between epinephrine, a potent LHRH agonist [(D-Ser-(TBu)6, des-Gly-NH2(10)) LHRH ethylamide: Buserelin] and hCG in normal and in vitro hCG-desensitized rat immature luteal cells in monolayer culture, on basal, hCG or cholera toxin stimulated intracellular and extracellular cyclic AMP and progesterone secretion. The present report shows that incubation of immature rat luteal cells in monolayer culture with Buserelin, led to 25-50% inhibition of the epinephrine--as well as PGE2--induced cyclic AMP and progesterone responses. The LHRH agonist can also reverse the stimulatory effects of cholera toxin in the presence of hCG and led with PGF2 alpha, to additive inhibitory effects on extracellular cyclic AMP accumulation induced by cholera toxin. Both Buserelin and PGF2 alpha can reverse the hCG-induced cyclic AMP and progesterone release but no effect could be observed when the incubation was carried out with either substance in the absence of hCG. Prostaglandin E2, in acute conditions of incubation, seems to share agonist properties with hCG when both were incubated with luteal cells. Buserelin reversed the stimulatory effects of PGE2, hCG, epinephrine, and cholera toxin on cyclic AMP and progesterone responses to these substances. These results suggest that Buserelin and PGF2 alpha have luteolytic-like effects and that there may be a complementary action for the two substances. Preincubation of rat luteal cells in monolayer culture with 1 nM hCG for a 24 h period led to the inhibition of cyclic AMP and progesterone responses after a subsequent exposure to hCG and epinephrine. Luteal cells were no longer responsive to hCG while the presence of epinephrine in hCG-desensitized cells led to a 40% stimulation of cAMP and progesterone production. These observations suggest that there occurred a partial alteration of the N component activity of the adenylyl cyclase system.
Assuntos
Corpo Lúteo/metabolismo , AMP Cíclico/biossíntese , Progesterona/metabolismo , Animais , Busserrelina/farmacologia , Células Cultivadas , Toxina da Cólera/farmacologia , Gonadotropina Coriônica/farmacologia , Corpo Lúteo/efeitos dos fármacos , Dinoprosta , Dinoprostona , Epinefrina/farmacologia , Feminino , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologia , Radioimunoensaio , Ratos , Ratos EndogâmicosRESUMO
To ascertain whether the immunoreactive luteinizing hormone (LH) levels measured following the combined treatment may represent cross-reaction of the LH antiserum with LH subunits, we have examined the effects of therapy on the serum levels of free alpha- and free LH-beta-subunits in intact, castrated, and estrogen-treated patients. In previously untreated patients receiving the LHRH agonist [D-Trp6,des-Gly-NH2(10)]LHRH ethylamide in association with the pure antiandrogen Flutamide, serum-free alpha-subunit levels were stimulated from 0.09 +/- 0.02 to 3.10 +/- 0.84 ng/ml after 5 days, and declined slowly afterwards to 1.33 +/- 0.20 ng/ml after 3 months of combined treatment. In patients pretreated from 12 to 24 months (17.5 +/- 1.0 months) with diethylstilbestrol (DES) prior to receiving the combined therapy, free serum alpha-subunit concentration followed a similar pattern, rising from 0.22 +/- 0.03 to 1.78 +/- 0.28 ng/ml after 15 days of combined treatment, and declining thereafter to 0.81 +/- 0.10 ng/ml after 3 months. Free LH-beta-subunits were below the detection limit in most previously untreated patients and in all DES-treated patients. After correcting for the cross-reactivity of the alpha-subunit in the LH RIA, immunoassayable LH serum levels in previously untreated patients were only slightly reduced from 0.81 +/- 0.06 ng/ml before the onset of the combined treatment to 0.52 +/- 0.05 ng/ml after 3 months. On the contrary, bioactive serum LH levels were drastically inhibited from 0.43 +/- 0.04 to 0.03 +/- 0.01 ng/ml after the same duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anilidas/uso terapêutico , Carcinoma/sangue , Flutamida/uso terapêutico , Hormônio Liberador de Gonadotropina/fisiologia , Fragmentos de Peptídeos/sangue , Hormônios Adeno-Hipofisários/sangue , Neoplasias da Próstata/sangue , Pamoato de Triptorrelina/análogos & derivados , Antagonistas de Androgênios/uso terapêutico , Carcinoma/tratamento farmacológico , Castração , Subunidade alfa de Hormônios Glicoproteicos , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Hormônio Luteinizante/sangue , Masculino , Concentração Osmolar , Neoplasias da Próstata/tratamento farmacológico , Estimulação QuímicaRESUMO
A process for the production of bakers' yeast in whey ultrafiltrate (WU) is described. Lactose in WU was converted to lactic acid and galactose by fermentation. Streptococcus thermophilus was selected for this purpose. Preculturing of S. thermophilus in skim milk considerably reduced its lag. Lactic fermentation in 2.3x-concentrated WU was delayed compared with that in unconcentrated whey, and fermentation could not be completed within 60 h. The growth rate of bakers' yeast in fermented WU differed among strains. The rate of galactose utilization was similar for all strains, but differences in lactic acid utilization occurred. Optimal pH ranges for galactose and lactic acid utilization were 5.5 to 6.0 and 5.0 to 5.5, respectively. The addition of 4 g of corn steep liquor per liter to fermented WU increased cell yields. Two sources of nitrogen were available for growth of Saccharomyces cerevisiae: amino acids (corn steep liquor) and ammonium (added during the lactic acid fermentation). Ammonium was mostly assimilated during growth on lactic acid. This process could permit the substitution of molasses by WU for the industrial production of bakers' yeast.
RESUMO
Although chronic treatment with luteinizing hormone-releasing hormone agonists achieves castration levels without side effects other than those related to hypoandrogenism, a limitation to their use alone for the treatment of prostatic cancer is the transient increase in serum androgens that lasts for 5 to 8 days at the start of treatment with the risk of disease flare. Our data show that the concomitant administration of the pure antiandrogen flutamide in association with the luteinizing hormone-releasing hormone agonist (D-Trp6) luteinizing hormone-releasing hormone ethylamide caused a 64 to 78 per cent decrease in serum prostatic acid phosphatase on days 3 and 7 after the start of treatment in 70 patients with previously untreated stage D2 prostatic cancer. Pain, which was present in 41 patients at the start of treatment, did not increase in any patient, it decreased in 7 at 1 week and it disappeared or decreased in 27 at 2 weeks. Performance, which originally was abnormal in 34 patients, became normal in 7 within 1 week and in 20 within 1 month (59 per cent). These data show that the addition of flutamide completely eliminates the risks of disease flare associated with the use of the otherwise exceptionally well tolerated luteinizing hormone-releasing hormone agonists in patients treated for prostatic cancer.